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Two approaches used for stem cell therapy for retinal disease
Physicians describe the regenerative and trophic approaches, both of which are in phase 1/2 trials.
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Stem cells are present in all multicellular organisms. They divide and differentiate into various specialized cell types and can self-renew to produce additional stem cells.
The two main types of stem cells are embryonic and adult. Embryonic stem cells are pluripotent and can differentiate into specialized cells and maintain normal turnover of regenerating organs (blood, skin, tissues in the intestine), while adult stem cells replenish adult tissues and function as a repair system for the body. The sources of human autologous stem cells include bone marrow, adipose tissue and blood.
The ability of stem cells to treat eye diseases is of great interest to both researchers and clinicians because currently there is no therapy to cure ocular neurodegenerative diseases. Ocular stem cells include limbal (corneal) stem cells, conjunctival stem cells and retinal stem cells located at the retinal ciliary margin. Additionally, extraocular stem cells appear promising in restoring vision loss. Extraocular stem cells include adult stem cells, induced pluripotent stem cells and embryonic stem cells. In the front of the eye, autologous limbal stem cells have the ability to regenerate corneal tissue that has been damaged. Autologous limbal stem cell transplants have been shown to regenerate, renewing the corneal epithelium and thus restoring normal vision in severely burnt eyes. In the back of the eye, there has been increasing interest in the potential for stem cell therapy to treat age-related macular degeneration, Stargardt’s macular dystrophy and other eye diseases.
Clinical milestones involving stem cells in the ocular arena include the well-established use of autologous limbal stem cells to treat stem cell-damaged corneas. In addition, according to a 2012 report, the use of human embryonic stem cell-derived cells, namely, human retinal pigment epithelium cells generated from embryonic stem cells, were transplanted subretinally in two patients, one with dry AMD and the other with Stargardt’s macular dystrophy. The transplanted cells seemed to attach to Bruch’s membrane, and both patients showed a degree of improved vision.
Although many questions remain to be answered by further research, these initial findings appear to be promising. Additional areas of interest include the use of implantable devices that are loaded with genetically modified cells, derived from human retinal cells that produce neurotrophic factor and promote the survival of photoreceptors and retinal ganglion cells.
In this column, Drs. Shah, Regillo and Ho describe the approaches to stem cell therapy for retinal disease.
Thomas “TJ” John, MD
OSN Surgical Maneuvers Editor
There are two main approaches regarding stem cell-based therapy for retinal disease, which requires implantation of cells in the subretinal space: regenerative and trophic. Here we will outline these two main approaches, which are currently in phase 1/2 trials in humans.
The regenerative approach is a strategy that utilizes a human embryonic stem cell (hESC) line that has been differentiated to retinal pigment epithelium (RPE) cells and offers a replacement for RPE cells lost in diseases such as geographic atrophy and Stargardt’s disease. In the trophic approach, undifferentiated human umbilical tissue-derived cells (hUTC) offer a means to support degenerating cells with paracrine effects from the transplanted cells through the release of various mediators (eg, interleukins, neurotropic factors).
Regenerative approach
The regenerative strategy has a long history of preclinical animal work. Various studies have demonstrated both the promise and proof of concept, while other studies have brought attention to important considerations such as immunologic graft rejection and/or graft survival, depending upon which type of stem cell line was utilized. A particular advance came with the purification of an hESC line by Advanced Cell Technology (ACT). The hESC line offers advantages over other stem cell lines in that these cells can be differentiated to provide a theoretically unlimited number of RPE cells for implantation.
The ACT approach is a transvitreal implantation of hESC-derived RPE cells that utilizes a standard 23- or 25-gauge pars plana vitrectomy with induction of a posterior vitreous detachment. A 41-gauge subretinal cannula is then used to create neurosensory localized retinal detachment adjacent to the site of geographic atrophy with balanced salt solution. Following formation of the subretinal “bleb,” a 38-gauge subretinal cannula is utilized to deliver the hESC-derived RPE cells. The current trial is a dose-escalation safety trial in which 50,000 to 200,000 hESC-derived RPE cells in 150 µL volume are delivered to the subretinal space. After an inspection of the peripheral retina, a fluid-air exchange is performed. The patient is then held in the supine position for 4 to 6 hours.
Figure 1. Regenerative stem cell approach to treating advanced geographic atrophy with the formation of a subretinal bleb to accommodate injection of hESC-derived RPE cells in and around the area of RPE atrophy.
Image: Schwartz SD
Unique to this protocol is the use of systemic immunosuppression. The protocol entails a detailed and thorough medical screening to identify eligible and healthy individuals in whom systemic immunosuppression would be appropriate. Immunosuppression is thought to be necessary in the perioperative period because this is the time frame for potential breakdown of the blood-retinal barrier, increasing the possibility of immunologic graft rejection as the eye is healing from surgery. It is hoped that ongoing, long-term immunosuppression will not be needed. Perioperative immunosuppression consists of CellCept (mycophenolate, Genentech) and Prograf (tacrolimus, Astellas Pharma) starting 1 week before surgery, with both agents continued until the sixth postoperative week. Mycophenolate is continued for 6 additional weeks, with no immunosuppression thereafter.
Trophic approach
There have been multiple trophic-based strategies that have shown efficacy in cell-based therapy; the approach with hUTC has been evaluated in the rat model of retinal dystrophy and has been found to rescue degenerating photoreceptors better than other cell lines (placenta-derived cells, mesenchymal stem cells and dermal fibroblasts). The current surgical trial for geographic atrophy utilizes an undifferentiated hUTC line, which was developed by Janssen, a division of Johnson & Johnson. This is a dose-escalating safety and feasibility study.
The surgical technique entails a transscleral microcatheter-based delivery of the hUTC line to the subretinal space adjacent to the region of geographic atrophy. After a limited conjunctival dissection with surface cautery, a scleral cut-down is performed with a Beaver blade approximately 9 mm posterior to the limbus. The sclera is then retracted with a specialized scleral speculum that is sutured in place to allow for the eventual advancement of a 250-µm subretinal microcatheter (iScience Interventional). After choroidal perforation, a subretinal bleb is created with Healon (sodium hyaluronate, Abbott Medical Optics) under direct visualization endoscopically (Endo Optiks). The microcatheter is then advanced through this opening in the subretinal space posteriorly. The catheter has an illuminated tip to allow for precise localization, adjacent to the region of geographic atrophy, under the view of the endoscope. A high-precision pump is then used to inject the hUTC line into the subretinal space. The catheter is carefully withdrawn, and all sclerotomies are closed with standard techniques.
Immunosuppression is not thought to be necessary for the survival of this particular cell line. Another key difference is that a transscleral approach for stem cell implantation is necessary with the hUTC line. Preclinical investigations found a higher rate of progression toward proliferative vitreoretinopathy (PVR) when a transvitreal approach was used. It may be that the undifferentiated nature of the hUTC line makes the progression to PVR more likely when a retinal break is present; thus, a transscleral approach is preferred. Phase 1 data are forthcoming in the fall.
After the safety of the cell lines and their respective surgical delivery approaches have been established, phase 1 data analyzing potential effects at the various cell doses will then be used to design the appropriate phase 2 studies for these stem cell therapies. It is projected that phase 2 testing will be under way within the next 1 to 2 years.